Polyhalomethyl pregnenes



United States Patent 3,151,132 POLYHALOMETHYL PREGNENES Albert Bowersand John Edwards, Mexico City, Mexico, assignors, by mesne assignments,to Syntex Corporation, a corporation of Panama No Drawing. Filed Oct.18, 1960, Ser. No. 63,266 Claims priority, application Mexico July 2,1960 15 Claims. (Cl. 260--397.3)

The present invention relates to novel cyclopentanophenauthrenecompounds and to a novel process for the production thereof.

More particularly the present invention relates to the novell6a-rnonofluoromethyl, 16a-difiuoromethyl and 16a-trifluoromethylderivatives of A -pregnene-3,20-dione and of A -pregnen-3fi-ol-20-one,to esters thereof and to a novel process for the preparation thereof.

The novel compounds of the present invention are useful as hypnoticagents and in the treatment of premenstrual tension as well as possessanti-fungal and antibactericidal properties. In addition, the novelcompounds are valuable intermediates for the preparation of the novelprogestational and cortical hormones having a trifiuoromethyl group,difluoromethyl group or monofiuoromethyl group at C-16 as described incopending applications Serial No. 63,265, and Serial No. 63,267 filed ofeven date.

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The novel compounds of the present invention may be represented by thefollowing formulas:

In the above formulas, X represents the monofluoromethyl, difluoromethylor trifluorornethyl group, and R represents hydrogen or the acyl groupof a hydrocarbon carboxylic acid of less than 12 carbon atoms, saturatedor unsaturated, of straight, branched, cyclic or cyclic-aliphatic chain,aromatic and may be substituted by functional groups such as hydroxy,acyloxy or up to 8 carbon atoms, alkoxy of up to 5 carbon atoms, amino,nitro or halogen. Typical ester groups are the acetate, propionate,buty-rate, enanthate, trimethylacetate, t-butylacetate, phenoxyacetate,cyclopentylpropionate aminoacetate and ,B-chloropropionate.

The novel compounds of the present invention may be prepared by aprocess illustrated by the following equation (for the C16-trifiuoromethyl compounds):

(l) NaBH,

(2) Etherification (1) KOH-Methanol (2) Benzoylation I CHO o (1)HCl-Acetic Acid (2) Acylation KOH-Me mg l Acylation In the aboveequation, Ac represents acetyl but other acyl groups derived from thehydrocarbon carboxylic acids described heretofore may be employed; Bzrepresents the benzoyl radical and R represents the acyl group of ahydrocarbon carboxylic acid of the type heretofore described.

In practicing the process outlined above, 16a-cyano- A-pregnen-3fl-ol-20-one acetate (I), described by J. Romo, Tetrahedron 3,37 (1958), is reacted with sodium borohydride to reduce the C- ketogroup to the (F20 hydroxyl group which is then etherified by reactionwith dihydropyran in benzene solution and in the presence ofp-toluenesulfonic acid. The thus formed20,8-tetrahydropyranyloxy-16a-cyano-A -pregnen-3fi-ol acetate (II) isthen hydrolyzed by refluxing with methanolic potassium hydroxide,followed by benzoylation as by conventional reaction with benzoylchloride in pyridine solution to afford3-benzoyloxy-ZOfl-tetrahydropyranyloxy- A -pregnen-16zx-carboxylic acid(III). Hydrolysis of the other group as by reaction of the lattercompound in acetic acid with dilute hydrochloric acid, followed byacylation, particularly acetylation, of the thus formed C-ZOB-alcohol byconventional means, affords Bari-benzoyloxy-ZOfi-acetoxy A pregnene 16Bcarboxylic acid (IV). Upon heating the latter compound in benzenesolution at 145 Coin a sealed tube for a period of time in the order of5 hours or keeping at room temperature for 96 hours, there is formed16a-trifiuoromethyl-A pregnene-36,20,8-diol-3-benZoate-2O-acetate (V)."The acetate group is saponified by treatment with methanolic potassiumcarbonate, followed by oxidation of the thus formed C-20 hydroxyl groupwith 8 N chromic acid to produce 16a-trilluoromethyl-A-pregnen-3B-ol-20-one benzoate (VI), which upon saponification withmethanolic potassium hydroxide is converted into 16a-trifluoromethyl-A-pregnen--ol-20-one (VII). By reaction with hydrocarbon carboxylic acid'anhydrides or chlorides of less than 12 carbon atoms, there are formedthe corresponding esters of the aforementioned 16a-triflu0romethyl-A-pregnen-3,6-ol-20-one (VIII). Oxidation of 16u-trifiuoromethyl-Apregnen-3fl-ol-20-one, under Oppenauer conditions gives16a-trifluoromethyl progesterone The preparation of the novel compoundsof the present invention having a difluoromethyl group at C-16a are(VII) produced by a process illustrated by the following C (X11) Q Q omIn the above formulas, Bz, Ac and R have the same 70 meaning as setforth above.

In carrying out the process outlined above, 3-benzoyloxy-20B-acetoxy-A-pregnene-16,8-carboxylic acid (IV) is treated with oxalyl chloride orthionyl chloride followed by reduction of thus formed acid chloride with75 lithium aluminum tertiary butoxide in tetrahydrofuran at 75 or by themethod of Rosenmund to form the 3- benzoate-ZO-acetate ofM-pregnene-ZtBQOB-diol-l6u-carboxaldehyde (X). The latter compound isthen reacted with a large excess of sulfur tetrafluoride in benzenesolution for a period of time in the order of 48 hours to efiectreplacement of the l6u-carboxaldehyde group by the difluorornethyl groupand thus form la-difluoromethyl-M-pregnene-B[3,20fl-diol-3-benzoate 20acetate (XI). The acetate group is preferentially saponitied as bytreatment with methanolic potassium carbonate followed by oxidation ofthe thus formed C-ZO alcohol with 8 N chromic acid to provide16a-difluoromethyl-A pregnen-3B-ol-20-one benzoate (XII: R benzoyl),which upon saponification with methanolic potassium hydroxide isconverted into 16a-difiuoromethyl-A -pregnen-3flol-20-one (XII: R=H).The latter compound is subjected to oxidation under Oppenauer conditionsto thus form l6a-difluoromethyl progesterone (XIII).

The preparation of the novel compounds of the present invention having amonofluoromethyl group at C16cz is illustrated by the followingequation:

1.031 1 Inc 5 (XVII) (XVI) In the above equation, Ac and R have the samemeaning as previously described.

In practicing the process outlined above, 3B-acetoxy- A-pregnadien-2O-one (XIV) is reacted with an excess of a monofiuoromethylmagnesium halide, preferably nionofiuoromethyl magnesium iodide, in asolvent such as tetrahydrofuran or diethyl ether in the absence orpresence of a catalyst such as cuprous chloride at a temperature in theorder of 30 C. to (1., preferably between 20 C. and l0 C. for a periodof time ranging from minutes to 2 hours. The reaction mixture is thentreated with aqueous ammonium chloride and there is formed withsimultaneous hydrolysis of the acetoxy groupl6wmonofiuoromethyl-M-pregnen-3fi-ol- 20-one (XV), which upon oxidationunder Oppenauer conditions is converted intoi6u-monofluoromethyl-progesterone (XVI).

By the reaction of 16a-monofluorornethyl-M-pregnen- -ol-20-one (XV) withhydrocarbon carboxyiic acid anhydrides of less than 12 carbon atoms,there are formed the corresponding esters (XVII).

By substituting the monofluoromethyl magnesium halide by trifluoromethylmagnesium halide in the above process, which is disclosed in ourcopending application Serial No. 63,265, filed of even date, there areformed 16a-trifluoromethyl-A -pregnen-3[3-ol-2tl-one, the esters thereofand l6a-trifiuoromethyl-progesterone.

Alternatively the novel compounds of the present invention having amonofiuoromethyl group at C-16a may g be prepared by a processillustrated by the following equation:

CH3 CH2 w CHOAo i CHOH J ROQU; oi)

In the above formulas Ac, Bz and R have the same meaning as previouslyset forth; Tos represents the tosyl radical.

In practicing the process just outlined, the 3-benzoate- ZO-acetate ofM-pregnene-SBJQB-diol-l6or-carboxaldehyde (X) is treated with sodiumborohydride to eifect reduction of the aldehyde group and thus form the3-benzoate- ZO-acetate of 16a-hydroxymethyl-M-pregnene-3,8,20-diol. Upontreatrnent with p-toluenesulfonic acid chloride in pyridine solution,the tosylate XVIII is formed which upon reaction with an alkali metalfluoride such as potassium hydrogen fluoride in dimethylformamidesolution is converted into the 3-benzoate-20-acetate of16a-monoflu0romethyl-A -pregnene-3fi,2OB-diol (XIX). The ace toxy moietyat 0-20 is preferentially hydrolyzed as by treatment with potassiumcarbonate to form the 3-benzoate of 16a-monofluoromethyl-A-pregnene-3(3,20fi-diol (XX) which is then oxidized with 8 N chromicacid to produce the S-benzoate of l6a-rnonofiuoromethyl-npregnen-Zvfl-ol-ZO-one. Upon saponitication with methanolic potassiumhydroxide the latter compound is converted into 16a-monofiuoromethyl-A-pregnen-3[3-01-20- one (XXI: R=H) which can be reestcrified withhydrocarbon carboxylic acid anhydrides to form other esters thereof(XXI: R acyl). Oxidation of 16anonofiuorornethyl-M-pregnen-3,8-ol-2()one (XXI:R=II) under Oppenauerconditions gives 16ot-monofluoromethyl-progesterone (XXII).

The following examples serve to illustrate but are not intended to limitthe scope of the present invention:

Example I To 1.0 g. of 16a-cyano-A -pregnen-3B-ol-ZD-one acetate in cc.of dioxane was added 500 mg. of sodium borohydride in a mixture of 1 cc.of water and 9 cc. of dioxane. After standing at room temperature for 2hours, water was added to the reaction mixture and the product thatseparated was filtered. This product, without further in the mixture.

purification, was dissolved in 150 cc. of benzene containing 3 cc. ofdihydropyran and 250 mg. of p-toluenesulfonic acid. After 20 hours atroom temperature the benzene solution was washed with 5% sodiumcarbonate solution and finally with water. Removal of the solvent andcrystallization from aqueous methanol afforded 3,8- acetoxy 20ptetrahydropyranyloxy-l6a-cyano-A -pregnene.

Example 11 1.0 g. of the above compound was refluxed for 10 hours with50 cc. of 4% methanolic potassium hydroxide solution and thenneutralized with acetic acid. Removal of the solvent under reducedpressure afforded 20B-tetrahydropyranyloxy Apregnen-Bfl-ol-l6oc-carboxylic acid which was used for the next stepwithout further purification.

Example III The above compound in 10 cc. of pyridine was treated with anexcess of benzoyl chloride and allowed to remain at room temperature for16 hours to finally furnish 3pbenzoyloxy ZOB-tetrahydropyranyloxy-h-pregnene-16acarboxylic acid.

Example IV Example V 2 g. of the above compound in 50 cc. of dry dioxanewas placed in a steel tube and cooled to -75 C. 2 g. of sulfurtetrafluoride was then added and the tube was sealed by means of a steelscrew cap. The tube and contents were then heated at 145 C., for 5hours, or preferably maintained for 96 hours at room temperature (20C.).

'After cooling, the contents were poured into water and the product wasisolated by extraction with ethyl acetate. Chromatography over aluminaafforded la-trifluoromethyl-A-pregnene-35,20fi-diol-3-benzoate-2Q-acetate.

Example VI The above compound was preferentially hydrolyzed at C2() byadding 1 molar equivalent of potassium carbonate dissolved in a littleWater to a solution of the above compound in methanol. The reactionmixture was kept at room temperature with stirring for 16 hours,

at the end of which, water was added, the mixture filtered and theproduct was chromatographed over alumina to yieldSfi-benzoyloxy-l6a-trifluoromethyl-M-pregnen-ZQB- Example VI] A solutionof 2 g. of the above compound in 100 cc. of acetone was cooled to C. andtreated under an atmosphere of nitrogen with stirring with a solution of8 N chromic acid until the color of the reagent persisted The oxidizingagent had been prepared by dissolving 26.7 g. of chromium trioxide in 23cc. of concentrated sulfuric acid and diluting with water to 100 cc.;the mixture was then stirred for 10 minutes more at room temperature,diluted with water and the precipitate was collected, washed with water,dried and recrystallized from ether, thus affording l6atrifiuorornethyl-3fl-benzoyloxy-A -pregnen-2O-one.

Example VIII The above compound was subjected to hydrolysis by treatmentwith 1% methanolic potassium hydroxide solution under reflux for 2 /2hours to furnish 16a-trifluoromethyl-A -pregnen-3fl-ol-ZO-one.

Reesterification of the hydroxyl group by conventional methods yieldedthe acetate, propionate and enanthate.

Example IX A solution of 3 g. of l6u-trifiuoromethyl-A -pregnen-Sfl-ol-ZO-one in 20 cc. of toluene and 50 cc. of cyclohexanone was driedby distilling off 30 cc. of the solvent. A solution of 3 g. of aluminumisopropoxide dissolved in 20 cc. of anhydrous toluene was then added andthe mixture was refluxed for 45 minutes; 10 cc. of acetic acid wereadded and the solvents removed by steam distillation. The product wasextracted several times with ethyl acetate and the organic extractsWashed with 5% hydrochloric acid solution, water, 10% sodium carbonatesolution and water until neutral, dried over anhydrous sodium sulfateand evaporated until crystallization started. There was thus obtainedl6a-trifiuoromethylprogesterone.

Example X A mixture of 1 g. of 35-benzoyloxy-2O/3-acetoxy-Apregnene-loa-carboxylic acid, obtained as described in Example IV and 5cc. of oxalyl chloride was refluxed under anhydrous conditions during 2hours. The solution was evaporated in vacuum, 2 portions of dry benzenewere added and reevaporated to eliminate traces of oxalyl chloride. Theabove crude acid chloride was dissolved in 20 cc. of anhydroustetrahydrofuran, cooled to -75 C. in a Dry ice-acetone bath and treatedwith a previously cooled solution of 600 mg. of lithium aluminumt-butoxide in 20 cc. of anhydrous tetrahydrofuran. The reaction mixturewas kept at 75 C. for 1 hour and then at room temperature for 30minutes, poured into ice water and extracted several times with ethylacetate, washed with water to neutral, dried over anhydrous sodiumsulfate and evaporated to dryness under vacuum. After chromatographythere was obtained the 3-benzoate-20- acetate of A-pregnene-3B,20fi-diol-lwcarboxaldehyde.

A solution of 500 mg. of the above aldehyde in cc. of benzene wastreated with 1 g. of sulfur tetrafiuororide and the mixture kept in asealed steel tube for 48 hours at room temperature, it was then pouredcarefully into ice water. An excess of sodium bicarbonate was added andthe product extracted with methylene chloride. The extract was washedwith water to neutral, dried and evaporated to dryness. Afterchromatography and crystallization of the solid fractions fromacetone-hexane there was obtained 16a-difiuoromethyl-A-pregnene-313,205- diol-3-benzoate-20-acetate.

For the next step there were combined several batches of the abovecompound.

Example XI A solution of 5 g. of 16u-difluoromethyl-A -pregnene-3{3,20f3-diol-3-benzoate-20-acetate in 200 cc. of methanol was treatedwith 2.5 g. of potassium carbonate dissolved in 20 cc. of water and themixture kept at room temperature for 12 hours. The reaction mixture wasneutralized with acetic acid and concentrated under vacuum to onethirdits volume, poured into water, the formed precipitate filtered, washedwith water to neutral and dried, thus giving 16a-difiuoromethyl-A-pregnene-3fi,20fl-diol-3-benzoate.

The above crude product was dissolved in 100 cc. of acetone, cooled to 0C. and treated dropwise under an atmosphere of nitrogen under stirringwith an 8 N chromic acid solution (prepared as in Example VII) until thecolor of the reagent persisted in the mixture, stirred for 10 minutesfurther at room temperature, diluted with water and the precipitatecollected, washed with Water and dried under vacuum, thus affordinglfia-difluorornethyl-A -pregnen-3fi-ol-20-one benzoate.

The crude benzoate was dissolved in 75 cc. of methanol and refluxed for3 hours with 2 g. of potassium hydroxide, it was then poured into icewater, the precipitate collected, washed with water to neutral, driedand recrystallized from ethyl acetate-ether, thus giving 3.5 g. of16oz-dlfiuoromethyl-A -pregnen-3fi-ol-20-one.

Conventional esterification of the above compound with the correspondingacid anhydrides or chlorides in pyridine solution gave the acetate,propionate and cyclopentylpropionate.

Example XII By following the method of Example IX, 5 g. of16adifiuoromethyhM-pregnen-3fl-ol-ZO-one were oxidized un der Oppenauerconditions thus giving l6a-difluoromethylprogesterone.

Example XIII To 150 cc. of tetrahydrofuran containing 3 g. ofmonofiuoromethylmagnesium iodide was added a solution of 5 g. of theacetate of A -piegnadien-3fl-ol-ZO-one in 50 cc. of tetrahydrofuran and0.7 g. of cuprous chloride. The addition was effected under stirring,over a period of 30 minutes, under an atmosphere of nitrogen and at atemperature between 20 C. and -10 C. The mixture was stirred for afurther 2 hours at C. There was then added 100 cc. of aqueous saturatedammonium chloride solution, the tetrahydrofuran was distilled and theaqueous residue extracted several times with ether. The extract waswashed with water, dried over anhydrous sodium sulfate and the ether wasevaporated. There was thus obtained l6a-monofluoromethyl-A-pregnen-318-01-20- one. Oppenaucr oxidation of the above compound, inaccordance with the method of Example IX gave 16%monofluoromethyl-progesterone. (The monofluoromethyl magnesium iodidewas prepared by treating fluoroiodomethane, described by Arkel andJanetsky, Rec. Trav. Chim. 56, 167 (1937), with magnesium according tothe method described by Haszeldine, J. Chem. Soc. 1275 (1954)).

Example XIV A solution of 1 g. ofl6u-monofiuoromethyl-M-pregnen-3fl-ol-20-one in 5 cc. of pyridine and 3cc. of propionic anhydride was allowed to stand at room temperatureovernight, the reaction mixture poured into ice water and the formedprecipitate collected by filtration, washed with water and dried. Therewas thus obtained the propionate of l6a-monofluoromethyl-A-pregnen-3[3-ol-20-one.

In a similar manner, but using the corresponding acid anhydrides orchlorides there were obtained the acetate, caproate, benzoate andcyclopentylpropionate of 16ccmonofluoromethyl-M-pregnen-Sfi-ol-ZO-one.

Example XV A solution of 500 mg. of sodium borohydride in 2 cc. of Waterwas added to a solution of 2 g. of the S-benzoate- ZO-acetate of A-pregnene-3p,20fl-diol-l6et-carboxaldehyde obtained as described inExample X, in 30 cc. of dioxane, and the mixture was allowed to standfor 3 hours at room temperature. The excess of reagent was decomposed byaddition of acetic acid, and then diluted with water. The product wasextracted with ethyl acetate and the extract was washed with water,dried and evaporated. The solid residue was purified by crystallizationfrom acetonehexane to give the S-benzoate-ZO-acetate ofl6e-hydroxymethyl-A -pregnene-3,8,20fi-diol.

A solution of the above compound in cc. of pyridine was treated with 2g. of tosyl chloride, and the mixture kept at 0 C. for 24 hours, pouredinto ice water, the formed precipitate collected, washed with water anddried, thus affording the l6ol-hydroxymethyl-tosylate,3-benzoate-ZO-acetate of M-pregnenedfiiQG-diol.

A solution of 1 g. of the above compound in cc. of dime'thylformamidewas treated with 1 g. of potassium hydrogen fluoride. The mixture washeated on the steam bath for 5 hours, poured into water, extracted withmethylene chloride and the organic extract washed several times withWater, dried over anhydrous sodium sulfate and evaporated to dryness.Crystallization from acetoneether gave 16a-rnonofiuoromethyl-A-pregnene-3fi,20B- diol 3-benzoate-20-acetate.

By following the methods of Examples VI, VII and VIII, the abovecompound was converted successively into3fl-benzoyloxy-l6a-monofluoromethyl A pregnen- 20301;3-benzoyloxy-1oer-monofluoromethyl-A -pregnen- 20-one and16a-monofluoromethyl-M-pregnen-S5-01-20- one. The latter compound wasidentical to that obtained in Example XIII.

We claim:

1. A compound of the following formula:

wherein R is selected from the group consisting of hydrogen and ahydrocarbon carboxylic acyl group of less than 12 carbon atoms and X isa difluoromethyl group.

2. 16a-difluoromethyl-A -pregnen-3/3-o1-2O-one.

3. 16a difluoromethyLAP-pregnen-3fi-ol-2Q-one benzoate.

4. l6a-difluoromethyl-A -pregnen-3li-ol-ZO-one acetate.

5. A compound of the following formula:

@53 may wherein X is selected from the group consisting of adifluoromethyl and a trifluoromethyl group.

6. 16ot-difiuoromethyl-progesterone.

7. 16a-trifluoromethyl-progesterone.

8. In the process of producing 16a-trifluoromethyl-Apregnen-Iili-ol-20one the steps comprising reducing ccyano-3fi-acyloXy-A-pregnen-20-one with an alkali metal borohydride, etherifying the thusformed 16a-cyano-3fiacyloxy-Mpregnen-ZOB-ol with dihydropyran,hydrolyzing the ZQfl-ether derivative with alcoholic alkali metalhydroxide to form the ZOE-ether of A -pregnene-3/3,20B-diol-la-carboxylic acid, benzoylating the latter product, hydrolyzingthe ether group with dilute mineral acid, acylating the thus formedC-20/3-hydroxyl group, treating the 3fi-benzoyloxy-2Ofi-acyloxy-A-pregnene-16a carboxylic acid with sulfur tetrafiuoride, selectivelyhydrolyzing the thus formed 16ix-trifiuoromethyl-3fl-benzoyloxy-2OB-acyloxy-M-pregnene with alcoholic alkali metal carbonate to form16oz-trifluoromethyl-3,B-benzoyloxy A pregnen- 203-01, and thereafteroxidizing with chromic acid and hydrolyzing with alcoholic metalhydroxide to form 160:- triiluoromethyl-A -pregnen-3,8-ol-20-one.

9. In the process of producing 16wtriiluoromethyl-Apregnen-ZaB-ol-ZO-one the step comprising heating 3510B- diacyloxy-A-pregnene-ldot-carboxylic acid with sulfur tetrafluoride.

10. The process of claim 9 wherein the reaction is maintained at 14-5 C.for five hours in a sealed tube.

11. The process of claim 9 wherein the reaction is maintained at 20 C.for 96 hours in a sealed tube.

12. The process of claim 9 wherein the 3a.,20fi-diacyloxy-A -pregnene16a carboxylic acid is 3 p benzoyloxy- 2O-acetoxy-A-pregnene-l6a-carb0xylic acid.

13. In the process of producing l6a-difluoromethyl-Apregnen-3B-ol-20-one the steps comprising reducing 16acyan-3,B-acyloxy-A-pregnen-2O-one With an alkali metal borohydride, etherifying the thusformed l6a-cyano-3flacyloxy-M-pregnen-ZOfi-ol with dihydropyran,hydrolyzing the ZOE-ether derivative with alcoholic alkali metalhydroxide to form the ZOfi-ether of A -pregnene-3Q,ZOB-diol-l6a-carboxylic acid, benzoylating the latter product, hydrolyzingwith ether group With dilute mineral acid, acylating the thus formedC-ZOfl-hydroxyl group, treating the3fl-benzoyloxy-20,B-acyloxy-M-pregnene-16a earboxylic acid with'oxalylchloride, reacting the thus formed 3fi-benzoyloxy-20fi-acyloxy-A-pregnene-16a carboxylic acid chloride with a reducing agent selectedfrom the group consisting of lithium aluminum tertiary butoxide andhydrogen, treating the thus formed SB-benzoyloxy- ZOfi-acyloxy-A-pregnene-16tx-carboxaldehyde with sulfur tetrafiuoride, selectivelyhydrolyzing the thus formed160cdifluoromethyl-3B-benzoyloxy-20fl-acyloxy A pregnene With alcoholicalkali metal carbonate to form 16OL-diflll0- romethyl-S/i-benzoyloxy-A-pregnen-ZOfi-ol and thereafter l 2. oxidizing With chromic acid andhydrolyzing with 'alcoholic alkali metal hydroxide to form t-dlfll101'0-methyl-A -pregnen-3fi-ol-ZO-one.

14. In the process of producing a l6ot-difluor0methyl derivative of thepregnane series the step comprising reacting a 20fl-acyloxy-A pregnene16a carboxaldehyde with an excess of sulfur tetrafluoride in an inertsolvent.

15. In the process of producing l6a-monofiuoromethyl-A-pregnen-3{3-ol-20-one the steps comprising reducing a 3,20-diacylate ofA -pregnene-3B,20-diol-16u-carboxaldehyde with sodium borohydride,forming the tosylate of the thus formed 3,20-diacylate ofl6ot-hydroxymethyl -A pregnene-3fl,20-diol, reacting the tosylate withan alkali metal fluoride to form the corresponding 3,20-diacylate ofl6ot-monofluoromethyl-h -pregnene 3fi,20fi diol and thereafterselectively hydrolyzing with alkali metal carbonate and oxidizing withchromic acid the last mentioned steroid to form the 3-acylate ofl6ot-monofluoromethyl-A -pregnen-3fi-ol-ZO-one.

References Cited in the file of this patent UNITED STATES PATENTS3,079,407 Sarett et al. Feb. 26, 1963

5. A COMPOUND OF THE FOLLOWING FORMULA: